The effects induced by the sulphonylurea glibenclamide on the neonatal rat spinal cord indicate a novel mechanism to control neuronal excitability and inhibitory neurotransmission

Abstract

Background and purpose: Using the neonatal rat spinal cord in vitro, we investigated the action of glibenclamide, a drug possessing dual pharmacological effects, namely block of K(ATP) channels and of the cystic fibrosis transmembrane conductance regulator (CFTR). Experimental approach: Intra- and extracellular recordings were performed on motoneurons and interneurons. RT-PCR and western immunoblotting were used to determine gene and protein expression. Key results: Glibenclamide (50 μM) facilitated mono- and polysynaptic reflexes, hyperpolarized motoneuron resting potential, increased action potential amplitude, decreased Renshaw cell-mediated recurrent inhibition, and increased network excitability by depressing GABA- and glycine-mediated transmission. The action of glibenclamide was mimicked by tolbutamide (500 μM) or the CFTR blocker diphenylamine-2,2-dicarboxylic acid (500 μM). The action of glibenclamide was independent from pharmacological inhibition of the Na +-K + pump with strophanthidin (4 μM) and was associated with a negative shift in the extrapolated reversal potential for CI - dependent synaptic inhibition. On interneurons, intracellularly-applied 8-bromo-cAMP elicited an inward current and resistance decrease; effects antagonized by the selective CFTR antagonist, CFTR inh-172 (5 μM). RT-PCR and western immunoblotting indicated strong expression of the CFTR in neonatal rat spinal cord. Conclusions and implications: These data suggest the CFTR expressed in motoneurons and interneurons of the neonatal spinal cord is involved in the control of Cl - homeostasis and neuronal excitability. CFTR appeared to contribute to the relatively depolarized equilibrium potential for synaptic inhibition, an important process to control hyperexcitability and seizure-predisposition in neonates. © 2007 Nature Publishing Group. All rights reserved.